Corticotropin-releasing hormone receptor-1 and 2 activity produces divergent resistance against stress-induced pulmonary Streptococcus pneumoniae infection

Abstract

Utilizing a murine model of S. pneumoniae infection and restraint stress, we determined how corticotropin releasing hormone (CRH-R) receptors impacts disease. CRH-R1 (antalarmin) and CRH-R2 (astressin2B) antagonists were administered intraperitoneally prior to restraint stress followed by pulmonary S. pneumoniae infection. CRH-R1 inhibition is not protective against pneumococcal disease induced by stress. Conversely, CRH-R2 inhibition attenuates stress-induced bacterial growth and significantly prevented severe sepsis. Neutrophillic responses were associated with CRH receptor-specific disease outcome providing a potential cellular target for stress-induced susceptibility to the development of severe pneumococcal disease. CRH receptor-mediated effects on immune responses could prove valuable for novel therapeutics.

Corticotropin-releasing hormone improves survival in pneumococcal pneumonia by reducing pulmonary inflammation

“…We have previously demonstrated a role for CRH in modulating leukocyte responses in lungs given restraint stress and S. pneumoniae infection (Kim et al. ). Specifically, those findings demonstrated divergent effects of CRH receptor antagonism on the influence of neutrophil and monocyte/macrophage infiltration to the lungs in response to infection.…”

“…administration of antalarmin, a CRHR1‐specific antagonist reduces survival using a model of aversive stress plus S. pneumoniae infection (Kim et al. ). Although changes in disease outcome were seen when antagonists were administered i.p., no studies have investigated how targeting CRH and CRHR1 activity in the respiratory tract impacts disease outcome.…”

“…Optimal doses of CRH (1 mg/kg), antalarmin (1 mg/kg), and dexamethasone (1 mg/kg) were administered by intranasal route based on previous published results (Kim et al. ).…”

“…; Kim et al. ). Determining the mechanism of action of CRH on particular inflammatory cells will provide a novel understanding of mechanisms mediating cellular immune inflammatory responses caused by severe bacterial infections.…”

“…However, its mechanisms of action on cellular immune function remain unclear. Importantly, few studies have demonstrated how CRH may impact innate pulmonary immune defenses against bacterial infections (e.g., Streptococcus pneumoniae) (Murray et al 2001;Gonzales et al 2008;Kim et al 2011). Determining the mechanism of action of CRH on particular inflammatory cells will provide a novel understanding of mechanisms mediating cellular immune inflammatory responses caused by severe bacterial infections.…”